The metabotropic glutamate receptors are known to contain one or more allosteric sites, which may alter the affinity with which glutamate and other metabotropic glutamate (mGluR) ligands bind to the primary binding or orthosteric sites. As the orthosteric binding site is highly conserved between all of the known metabotropic glutamate receptors, functional selectivity may best be achieved through allosteric interaction with the receptor.
Modulation of metabotropic glutamate receptor 2 (mGluR2), which is prevalent on presynaptic nerve terminals in the cortex and hippocampus and regulates the release of the brain's major excitatory neurotransmitter glutamate at key neural synapses, has been demonstrated to have a major role in cognitive processing. Neurodegenerative diseases and disorders affecting cognition are thought to be influenced by glutamate signaling. Such neurodegenerative diseases and disorders affecting cognition include (but are not limited to) various forms of dementia, including dementia of the Alzheimer's type (Alzheimer's disease), including mild, moderate, and severe Alzheimer's disease, mild cognitive impairment, and others. Such diseases and disorders may result in, or be identified by manifestations such as progressive memory impairment, loss of language and visuospatial skills, behavioral deficits and others. The potential for inhibition of mGluR2 to improve cognitive performance has been demonstrated genetically and pharmacologically in preclinical species (Higgins et al. [2004], Neuropharmacology 46, 907-917). Further, inhibition of mGluR2/3 with a negative allosteric modulator shows precognitive effects in non-human primates (Goeldner et al., [2013], Neuropharmacology 64, 337-346). Similarly, mGluR2 inhibition with negative allosteric modulators is expected to improve cognition and reverse dementia associated with other disorders, such as schizophrenia (Marek [2010], Eur J Pharmacol 639, 81-90) and general mild cognitive impairment, since enhancement of downstream glutamatergic signaling has been shown to improve cognition clinically (Lynch et al. [1997], Exp Neurol 145, 89-92). For these reasons, inhibitors of mGluR2 are believed to be useful in improvement of cognitive performance associated with various forms of dementia, including Alzheimer's disease, cognitive impairment associated with schizophrenia, and other diseases and disorders. Patents have been filed disclosing mGluR2/3 inhibitors for these (and other) indications (Celanire et al. [2015], Expert Opin Ther Patents 25, 69-90).
Given the capacity of presynaptic mGluR2 to modulate glutamate release, pharmacologic inhibition of mGluR2 with negative allosteric modulators has the capacity to enhance glutamate signaling to alleviate other disorders involving glutamate signaling. Among these are mood disorders including major depressive disorder (MDD), depression associated with bipolar disorder and anxiety. Inhibition of mGluR2 and mGluR3 by orthosteric antagonists have demonstrated efficacy in rodent models of depression (Chaki et al. [2004], Neuropharmacology 46, 457-67) as have negative allosteric modulators (Campo et al. [2011], J Neurogenet 25, 152-66). Antagonists of mGluR2 and mGluR3 have also demonstrated efficacy in rodent models of anxiety (Shimazaki et al. [2004], Eur J Pharmacol 501, 121-5; Iijima et al. [2007], Psychopharmacology (Berl) 190, 233-9) which has resulted in the filing of patents for mGluR2/3 inhibitors for these (and other) indications (Celanire et al. [2015], Expert Opin Ther Patents 25, 69-90).
Inhibition of mGluR2 receptors with negative allosteric modulators is also expected to modulate sleep and arousal and circadian timing of sleep wake cycles. Activation of mGluR2 with a positive allosteric modulator results in deep sleep in rats and clinically in healthy human volunteers (Ahnaou et al. [2016], Neuropharmacology 103, 290-305) such that inhibition with a negative allosteric modulator is expected to promote arousal coincident with improved cognition. Glutamate signaling modulated by group II mGluRs (mGluR2, mGluR3) is also involved in the circadian timing of sleep/wake cycles such that inhibition of mGluR2 may be expected to improve coordination of activity to environmental light/dark cycles. Genetic loss of mGluR2 and mGluR3 as well as pharmacological inhibition with negative allosteric modulators to these receptors results in enhanced responses to light entrainment cues (Pritchett et al. [2015], PLoS One 10, e0125523).
Inhibition of mGluR2 with negative allosteric modulator compounds is also expected to modulate pain sensation and responses to pain. Glutamate signaling mediates both the transmission of pain information as well as peripheral and central mechanisms of pain hypersensitivity such that modulation of this signaling via mGluR2 inhibition has the potential to impact nociception as well as the central perception of pain memory (Chiechio [2016], Adv Pharmacol 75, 63-89).
Certain substituted quinoline carboxamides, quinoline carbonitriles, tetrahydronaphthyridines, and others, are known in the art as mGluR2 inhibitors or for other uses. See, for example, WO2016/032921, WO2013/066736, US Patent Application No. 2008/0188521, WO2007/038865, WO 1996/13500, each disclosing compounds as leukotriene inhibitors, and Canadian Patent Application No. 2169231, disclosing compounds as leukotriene and SRS-A inhibitors. There remains a need in the art for novel compounds that are effective as non-competitive mGluR2 modulators, and/or mGluR2 negative allosteric modulators (NAMs).